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PRODUCT MONOGRAPH Pr DIOVAN®-HCT (valsartan and hydrochlorothiazide tablets) 80mg/12.5mg, 160mg/12.5mg, 160 mg/25 mg, 320mg/12.5mg tablets and 320mg/25mg tablets Angiotensin II AT1 Receptor Blocker and Diuretic Novartis Pharmaceuticals Canada Inc 385 Boulevard Bouchard Dorval, Quebec H9S 1A9 Date of Revision: May 12, 2015 Submission Control No: 181891 DIOVAN is a Registered Trademark Page 1 of 45 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3 INDICATIONS AND CLINICAL USE ..............................................................................3 WARNINGS AND PRECAUTIONS ..................................................................................4 ADVERSE REACTIONS..................................................................................................10 DRUG INTERACTIONS ..................................................................................................14 DOSAGE AND ADMINISTRATION ..............................................................................19 OVERDOSAGE ................................................................................................................20 ACTION AND CLINICAL PHARMACOLOGY ............................................................21 STORAGE AND STABILITY ..........................................................................................25 SPECIAL HANDLING INSTRUCTIONS .......................................................................25 DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................25 PART II: SCIENTIFIC INFORMATION ...............................................................................27 PHARMACEUTICAL INFORMATION..........................................................................27 CLINICAL TRIALS ..........................................................................................................28 DETAILED PHARMACOLOGY .....................................................................................28 TOXICOLOGY .................................................................................................................29 REFERENCES ..................................................................................................................36 PART III: CONSUMER INFORMATION..............................................................................37 Page 2 of 45 Pr DIOVAN®-HCT (valsartan and hydrochlorothiazide) PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Non-medicinal Ingredients Oral Tablets: 80mg/12.5mg 160mg/12.5mg 160mg/25mg 320mg/12.5mg 320mg/25mg Colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, talc, and titanium dioxide. Additional nonmedicinal ingredients for: DIOVAN®-HCT 80/12.5 mg tablets: red iron oxide and yellow iron oxide. DIOVAN®-HCT 160/12.5 mg tablets: red iron oxide. DIOVAN®-HCT 160/25 mg tablets: black iron oxide, red iron oxide and yellow iron oxide. DIOVAN®-HCT 320/12.5 mg tablets: black iron oxide and red iron oxide. DIOVAN®-HCT 320/25 mg tablets: yellow iron oxide. INDICATIONS AND CLINICAL USE DIOVAN®-HCT (valsartan and hydrochlorothiazide) is indicated for the treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate. DIOVAN®-HCT is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION). Patients should be titrated on individual drugs. If the fixed combination represents the dose and dosing frequency determined by this titration, the use of DIOVAN®-HCT may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary it is advisable to use the individual drugs. Geriatrics (> 65 years of age): No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out and appropriate caution is recommended. Page 3 of 45 Pediatrics (< 18 years of age): The safety and efficacy of DIOVAN®-HCT in children and adolescents (below the age of 18 years) have not been established and use in this age group is not recommended. CONTRAINDICATIONS DIOVAN®-HCT (valsartan and hydrochlorothiazide) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container (see DOSAGE FORMS, COMPOSITION AND PACKAGING). Because of the hydrochlorothiazide component, it is also contraindicated in patients with anuria, severe progressive renal disease and if increasing azotemia and oliguria occur during treatment. Patients who are hypersensitive to other sulfonamide-derived drugs. DIOVAN®-HCT is also contraindicated in pregnant and nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women). Thiazide diuretics are contraindicated in patients with hyponatremia, hypercalcemia, symptomatic hyperuricemia, and conditions involving enhanced potassium loss. Concomitant use of angiotensin receptor antagonists (ARBs) - including valsartan - or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR <60ml/min/1.73m2) is contraindicated (see WARNINGS AND PRECAUTION, General, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal and DRUG INTERACTIONS, Drug-Drug Interactions, Dual Blockade of the Renin-AngiotensinSystem (RAS) with ARBs, ACEIs, or aliskiren) WARNINGS AND PRECAUTIONS Serious Warnings and Precautions When used in pregnancy, angiotensin receptor (AT1) blockers (ARB) can cause injury to or even death of the developing fetus. When pregnancy is detected, DIOVAN®-HCT should be discontinued as soon as possible (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations). Angioedema Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients treated with valsartan: some of these patients previously experienced angioedema with other drugs including ACE inhibitors. DIOVAN® -HCT should be immediately discontinued in patients who develop angioedema, and DIOVAN® -HCT should not be re-administered. If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, DIOVAN®-HCT should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves Page 4 of 45 without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 to 0.5 ml of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS - Post Marketing Adverse Drug Reactions). Patients with a known hypersensitivity (anaphylaxis) or angioedema to ARBs should not be treated with DIOVAN®-HCT (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). Cardiovascular Hypotension Occasionally, symptomatic hypotension has occurred after administration of valsartan, in some cases after the first dose. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. Valvular Stenosis There is concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion when treated with vasodilators, because they do not develop as much after load reduction. Dual Blockade of the Renin-Angiotensin System (RAS) There is evidence that co-administration of angiotensin receptor antagonists (ARBs), including valsartan, or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR<60ml/min/1.73m2). Therefore, the use of DIOVAN®-HCT in combination with aliskiren-containing drugs is contraindicated in these patients. Co-administration of ARBs, including DIOVAN®-HCT, with other agents blocking the RAS such as ACEIs or aliskirencontaining drugs is not recommended in any patient, as adverse outcomes cannot be excluded. Endocrine and Metabolism Serum electrolyte changes Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, etc.) should be used with caution. Thiazide diuretics can precipitate new onset hypokalemia or exacerbate preexisting hypokalemia. Thiazide diuretics are contraindicated in patients with conditions involving enhanced potassium loss (refractory hypokalemia), for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. All patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium. Page 5 of 45 Thiazide diuretics can precipitate new onset hyponatremia and hypochloremic alkalosis or exacerbate pre-existing hyponatremia. Hyponatremia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Regular monitoring of serum sodium concentrations is recommended. Patients receiving thiazides should be carefully observed for clinical signs of fluid and electrolyte imbalance (hyponatremia, hypochloremic alkalosis and hypokalemia). Periodic determinations of serum electrolytes to detect possible electrolyte disturbance should be performed at appropriate intervals. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Other metabolic disturbances Like other diuretics, hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Thiazides are contraindicated in patients with symptomatic hyperuricemia. Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium in the absence of known disorders of calcium metabolism. Since hydrochlorothiazide can increase serum calcium concentrations, it should not be used (see Contraindications) in patients with hypercalcemia. Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic clarification is necessary and thiazides should be discontinued. Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability). Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances, when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Thiazides may decrease serum PBI levels without signs of thyroid disturbance. Increases in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy, including hydrochlorothiazide. Page 6 of 45 Hepatic/Biliary/Pancreatic Hydrochlorothiazide should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance or of serum ammonia may precipitate hepatic coma. In general, no dosage adjustment is needed in patients with mild to moderate liver disease. Due to the hydrochlorothiazide component, DIOVAN®-HCT should not be used (not recommended) in patients with severe hepatic impairment (see DOSAGE AND ADMINISTRATION, Hepatic impairment). However, care should be exercised in patients with liver disease, especially in those patients with biliary obstructive disorders, as the major portion of valsartan is eliminated in the bile. No information is available in patients with severe liver disease (see ACTION AND CLINICAL PHARMACOLOGY-Pharmacokinetics). Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Ophthalmologic Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute-angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. Renal As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk. The incidence of clinically relevant hyperkalemia has also been observed to be increased with valsartan (see ADVERSE REACTIONS - Laboratory Findings). Patients exposed to potassiumsparing diuretics and/or potassium supplements were more likely to develop hyperkalemia. Accordingly, their use should be carefully monitored or avoided (see DRUG INTERACTIONS Agents Increasing Serum Potassium). Page 7 of 45 Some patients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potassium. These effects are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of DIOVAN®-HCT may be required. In the Valsartan Heart Failure Trial, in which 93% of patients were on concomitant ACE inhibitors, treatment was discontinued for elevations in creatinine or potassium in a total of 1.0% on valsartan vs. 0.2% on placebo. Use of valsartan should include appropriate assessment of renal function. No dosage adjustment is required for patients with mild to moderate renal impairment (GFR ≥30 mL/min). Because of the hydrochlorothiazide component, DIOVAN®-HCT (valsartan and hydrochlorothiazide) should not be used in patients with severe renal impairment (GFR<30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease (see CONTRAINDICATIONS). They are ineffective as monotherapy in severe renal impairment (GFR<30 mL/min) (see DOSAGE AND ADMINISTRATION, renal impairment, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). Azotemia Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued (see CONTRAINDICATIONS). Patients with renal impairment The use of ARBs – including valsartan – or of ACEIs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR <60ml/min/1.73m2) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Drug-Drug Interactions, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs, or aliskiren-containing drugs). Sensitivity/Resistance Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide. Special Populations Pregnant Women: Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, DIOVAN®-HCT (valsartan and hydrochlorothiazide) should be discontinued as soon as possible. The use of ARB is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current Page 8 of 45 evidence available on the risk with ARB, similar risks may exist for this class of drugs. Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started. The use of ARBS during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan. Infants with histories of in utero exposure to ARBs should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. Valsartan is not removed from plasma by dialysis. Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics, including hydrochlorothiazide in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse experiences which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia. Animal Data: No teratogenic effects were observed when valsartan was administered orally to pregnant mice and rats at doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate and slight delays in developmental milestones were observed in studies in which parental rats were treated orally with valsartan at maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. Nursing Women: It is not known whether valsartan is excreted in human milk but significant levels have been found in the milk of lactating rats. Thiazides appear in human milk. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatrics (< 18 years of age): The safety and efficacy of DIOVAN®-HCT in children and adolescents (below the age of 18 years) have not been established and use in this age group is not recommended. Geriatrics (> 65 years of age): No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out and appropriate Page 9 of 45 caution is recommended. ADVERSE REACTIONS Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. DIOVAN®-HCT (valsartan and hydrochlorothiazide) has been evaluated for safety in more than 7616 patients treated for essential hypertension. Of these, 4372 were treated with DIOVAN®HCT in controlled clinical trials with a mean exposure of 8 weeks. In controlled clinical trials, discontinuation due to Adverse Experiences (AEs) occurred in 2.3 % and 3.1 % of patients treated with DIOVAN®-HCT and placebo, respectively. The most common AEs resulting in discontinuation of therapy with DIOVAN®-HCT were dizziness and headache. The most common serious AEs with DIOVAN®-HCT were myocardial infarction and chest pain. The following table is based on double-blind, active or placebo-controlled trials in patients treated with DIOVAN®-HCT at doses of 80mg/12.5mg, 80mg/25mg, 160mg/12.5mg, 160mg/25mg, 320mg/12.5mg and 320mg/25mg, DIOVAN at doses of 80mg, 160mg, and 320 mg, and HCT at doses of 12.5mg and 25mg (see CLINICAL TRIALS). The table includes all AEs with an incidence of 1% or greater in either the DIOVAN®-HCT, DIOVAN® monotherapy, HCT monotherapy, or placebo group, irrespective of causal relationship to study drug. Table 1 - Occurrence of adverse events during double-blind controlled trials in patients treated with DIOVAN®-HCT at doses of 80mg/12.5mg, 80mg/25mg, 160mg/12.5mg, 160mg/25mg, 320mg/12.5mg and 320mg/25mg. Ear and Labyrinth disorders Vertigo Gastrointestinal disorders Diarrhoea Nausea Dyspepsia Valsartan / HCTZ N= 4372 n (%) Valsartan N= 2447 n (%) Hydrochlorothiazid e N= 535 n (%) Placebo N= 262 n (%) 35 (0.8) 10 (0.4) 6 (1.1) 1 (0.4) 48 (1.1) 37 (0.8) 25 (0.6) 41 (1.7) 21 (0.9) 18 (0.7) 10 (1.9) 10 (1.9) 6 (1.1) 3 (1.1) 4 (1.5) 1 (0.4) Page 10 of 45 Vomiting Toothache Constipation General Disorders Fatigue Oedema Peripheral Infections Nasopharyngitis Upper respiratory tract infection Influenza Bronchitis Sinusitis Urinary tract infection Metabolic and nutrition disorders Hypokalaemia Musculoskeletal and connective tissue disorders Back pain Arthralgia Myalgia Pain in extremity Muscle cramp Nervous system disorders Headache Dizziness Somnolence Hypoaesthesia Sinus headache Migraine Psychiatric disorders Insomnia Renal and urinary disorders Pollakiuria Respiratory, thoracic and mediastinal disorders Cough Pharyngolaryngeal pain Sinus congestion Nasal congestion Skin and subcutaneous tissue disorders 13 (0.3) 9 (0.2) 6 (0.1) 11 (0.4) 4 (0.2) 3 (0.1) 1 (0.2) 1 (0.2) 12 (2.2) 4 (1.5) 3 (1.1) 2 (0.8) 72 (1.6) 25 (0.6) 26 (1.1) 27 (1.1) 22 (4.1) 10 (1.9) 4 (1.5) 3 (1.1) 103 (2.4) 53 (1.2) 67 (2.7) 49 (2.0) 15 (2.8) 23 (4.3) 5 (1.9) 9 (3.4) 37 (0.8) 33 (0.8) 29 (0.7) 26 (0.6) 22 (0.9) 15 (0.6) 23 (0.9) 12 (0.5) 8 (1.5) 6 (1.1) 7 (1.3) 7 (1.3) 3 (1.1) 3 (1.1) 6 (2.3) 1 (0.4) 7 (0.2) 2 (0.1) 13 (2.4) 2 (0.8) 52 (1.2) 44 (1.0) 25 (0.6) 21 (0.5) 18 (0.4) 37 (1.5) 25 (1.0) 15 (0.6) 10 (0.4) 3 (0.1) 11 (2.1) 8 (1.5) 6 (1.1) 11 (2.1) 10 (1.9) 7 (2.7) 3 (1.1) 1 (0.4) 0 (0.0) 3 (1.1) 161 (3.7) 153 (3.5) 11 (0.3) 10 (0.2) 4 (0.1) 2 (0.0) 126 (5.1) 49 (2.0) 8 (0.3) 5 (0.2) 7 (0.3) 7 (0.3) 54 (10.1) 27 (5.0) 1 (0.2) 2 (0.4) 3 (0.6) 0 (0.0) 38 (14.5) 10 (3.8) 3 (1.1) 4 (1.5) 3 (1.1) 4 (1.5) 16 (0.4) 12 (0.5) 3 (0.6) 3 (1.1) 30 (0.7) 11 (0.4) 8 (1.5) 2 (0.8) 52 (1.2) 30 (0.7) 19 (0.4) 16 (0.4) 37 (1.5) 12 (0.5) 7 (0.3) 14 (0.6) 11 (2.1) 6 (1.1) 12 (2.2) 7 (1.3) 2 (0.8) 1 (0.4) 3 (1.1) 0 (0.0) Page 11 of 45 Rash 11 (0.3) 10 (0.4) 6 (1.1) 1 (0.4) Evaluation of the AEs in the total active-, or placebo-controlled safety population, showed that the most common events, regardless of relationship to treatment in patients treated with valsartan 320 mg/HCTZ were, dizziness, nasopharyngitis, headache and fatigue. The incidence of hypotension was 0.7% in patients treated with valsartan 320mg/HCTZ. The following adverse reactions have been reported in patients treated with thiazide diuretics alone, including hydrochlorothiazide: Very common: mainly at higher doses, hypokalemia, blood lipids increased (total cholesterol and triglycerides). Common: Hyponatremia, hypomagnesemia, hyperuricemia, urticaria and other forms of rash, decreased appetite, mild nausea and vomiting, orthostatic hypotension, which may be aggravated by alcohol, anaesthetics or sedatives, and impotence. Rare: Hypercalcemia, hyperglycemia, glycosuria and worsening of diabetic metabolic state, photosensitivity reaction, abdominal discomfort, constipation, diarrhoea, cholestasis or jaundice, arrhythmias, headache, dizziness, sleep disorders, depression, paresthesia, visual impairment, thrombocytopenia, sometimes with purpura. Very rare: Hypochloremic alkalosis, vasculitis necrotising, toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, pancreatitis, leukopenia, agranulocytosis, bone marrow failure, haemolytic anaemia, hypersensitivity reactions, respiratory distress including pneumonitis and pulmonary oedema. Less Common Clinical Trial Adverse Drug Reactions (<1%) Body as a whole: arthritis, asthenia, hypersensitivity, influenza, contusion, insomnia, peripheral oedema, pyrexia, sprains and strains Cardiovascular: angina pectoris, hypotension, myocardial infarction, palpitations, tachycardia, ventricular systoles Digestive: motion sickness, stomach discomfort Ear and Labyrinth: ear pain Gastrointestinal: abdominal pain, dry mouth, dyspepsia, flatulence, gastritis, toothache, vomiting Muscoskeletal and connective tissue: arthralgia, myalgia, muscle strain Metabolic and Nutritional: diabetes mellitus, gout, hypokalaemia, hyperuricaemia Nervous system/Psychiatric: anxiety, somnolence Renal and urinary system: micturition frequency, urinary tract infection, pollakiuria Respiratory, thoracic, mediastinal: bronchitis, chest discomfort/pain, dyspnea pharyngolaryngeal pain, sinus congestion, sinusitis Reproductive: erectile dysfunction Skin and subcutaneous tissue: rash Special senses: blurred vision, conjunctivitis, vertigo, tinnitus, visual disturbance Other: viral infection Page 12 of 45 Abnormal Hematologic and Clinical Chemistry Findings Laboratory Findings: Potassium: In the double-blind, active or placebo-controlled trials potassium decrease of >20% was observed most frequently with HCTZ 25mg (9.7%), followed by HCTZ 12.5mg (6.3%), valsartan/HCTZ 320/25 mg (4.5%), valsartan 320/12.5 mg (3.8%), and valsartan 320mg (2.0%) compared to placebo (3.1%). Also some patients showed serum potassium increase >20 % but no dose relationship could be demonstrated. Creatinine/Blood urea nitrogen (BUN)/Uric acid: Minor elevations in creatinine and BUN occurred in 1.9% and 14.7%, respectively, of patients treated with DIOVAN®-HCT and 0.4% and 6.3%, respectively, of patients given placebo in controlled clinical trials. Uric acid increase of > 50% was observed most frequently with valsartan/HCTZ 320/25mg (5.5%), followed by valsartan/HCTZ 320/12.5mg (2.8%), HCTZ 25mg (2.0%), valsartan 320mg (1.7%), and HCTZ 12.5mg (0.8%) compared to placebo (1.6%). Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of patients treated with DIOVAN®-HCT compared with 0.0% of patients given placebo. Neutropenia: Neutropenia was observed in 0.1% of patients treated with DIOVAN®-HCT and 0.4% of patients treated with placebo. Post-Market Adverse Drug Reactions Other adverse reactions reported in post-marketing use of DIOVAN® alone include: anaphylaxis (very rarely), angioedema (involving swelling of the face, lips and/or tongue), dermatitis bullous (frequency unknown), photosensitivity, increase in blood pressure and taste disorders. Very rare cases of impaired renal function have also been reported. The following adverse drug reactions have also been identified based on post-marketing experiences. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies. Therefore, the frequency assigned is “not known”: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma. Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. Cases of syncope were reported with DIOVAN®-HCT. It is unknown whether these effects were causally related to the therapy. Cases of dehydration, dizziness postural, hypoesthesia, prutitus and rhinitis, leucopenia, abdominal pain upper, bronchitis acute, epistaxis, gastroenteritis, hyperhidrosis, neck pain, otitis media, paraesthesia, ligament sprain, hypersensitivity/allergic reactions including serum sickness, non-cardiogenic pulmonary oedema and libido decreased have also been reported. Page 13 of 45 Hepato-biliary disorders: Hepatic enzyme increased including blood bilirubin increased. The following serious adverse events, irrespective of causality and with unknown frequency, have been reported from clinical studies or post-marketing experiences: Toxic epidermal necrolysis (TEN), Stevens-Johnsons syndrome (SJS), erythema multiforme (EM), toxic skin eruption, skin necrosis, exfoliative rash, pemphigus and pemphigoid. DRUG INTERACTIONS Drug-Drug Interactions Table 2 – Established or Potential Drug-Drug Interactions for valsartan Proper Name Ref. Effect Clinical comment Monitor serum potassium Agents Increasing Serum T Concomitant use of potassiumlevel. Potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), or other drugs that can increase potassium levels (e.g., heparin, non-steroidal antiinflammatory [NSAID] drugs, trimethoprim-sulfamethoxazole), potassium supplements, or salt substitutes containing potassium, may lead to increases in serum potassium. Concomitant thiazide diuretic use may attenuate any effect that valsartan may have on serum potassium. Lithium CT, C Since valsartan decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or thiazides. Since renal clearance of lithium is reduced by thiazides, the risk Careful monitoring of serum lithium concentrations is recommended during concomitant use. Page 14 of 45 Non-Steroidal AntiInflammatory (NSAID) Drugs, including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) CT OATP1B1 and MRP2 Transporters T Warfarin CT of lithium toxicity may presumably be increased further with Diovan®-HCT. When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volumedepleted (including those on diuretic therapy), or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function. The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter, OATP1B1, and the hepatic efflux transporter, MRP2. Co-administration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan. Co-administration of valsartan and warfarin over 3 days did not affect the bioavailability of valsartan. Co-administration of valsartan and warfarin resulted in a 12% increase in prothrombin time (PT) but had no effect on activated partial thromboplastin time (APTT). See WARNINGS AND PRECAUTIONS, General, Dual Blockade of the ReninAngiotensin System (RAS). Monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly. Monitor blood pressure as per routine. Interaction is not clinically relevant. Monitor PT as per routine. Dual blockade of the CT Renin-AngiotensinSystem (RAS) with ARBs, ACEIs, or aliskiren-containing drugs Legend: C = Case Study; CT = Clinical Trial; T = Theoretical Page 15 of 45 Table 3 – Established or Potential Drug-Drug Interactions for hydrochlorothiazide Proper Name Ref. Effect Clinical comment Alcohol, barbiturates, or C Potentiation of orthostatic Avoid alcohol, narcotics hypotension may occur. barbiturates or narcotics, especially with initiation of therapy. Amantadine C Co-administration of thiazide Monitor for adverse diuretics (including effects of amantadine. hydrochlorothiazide) may increase the risk of adverse effects caused by amantadine. Amphotericin B T Amphotericin B increases the Monitor serum potassium risk of hypokalemia induced by level. thiazide diuretics Antidiabetic agents (e.g. CT Thiazide-induced hyperglycemia Monitor glycemic control, insulin and oral may compromise blood sugar supplement potassium if hypoglycemic agents) control. Depletion of serum necessary, to maintain potassium augments glucose appropriate serum intolerance. potassium levels, and adjust diabetes medications as required. Antihypertensive drugs CT Hydrochlorothiazide may potentiate the action of other antihypertensive drugs (e.g. guanethidine, methyldopa, betablockers, vasodilators, calcium channel blockers, ACEI, ARB, and direct renin inhibitors). Antineoplastic drugs, including cyclophosphamide and methotrexate C Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects. Bile acid sequestrants, eg. cholestyramine CT Calcium and vitamin D supplements C Bile acid sequestrants bind thiazide diuretics in the gut and impair gastrointestinal absorption by 43-85%. Administration of thiazide 4 hours after a bile acid sequestrant reduced absorption of hydrochlorothiazide by 3035%. Thiazides decrease renal excretion of calcium and increase calcium release from Hematological status should be closely monitored in patients receiving this combination. Dose adjustment of cytotoxic agents may be required. Give thiazide 2-4 hours before or 6 hours after the bile acid sequestrant. Maintain a consistent sequence of administration. Monitor blood pressure, and increase dose of thiazide, if necessary. Monitor serum calcium, especially with concomitant use of high Page 16 of 45 bone. Carbamazepine C Corticosteroids, and adrenocorticotropic hormone (ACTH) T Cyclosporine C Diazoxide C Digoxin CT Drugs that alter GI motility, i.e., anticholinergic agents, such as atropine and prokinetic agents, such as metoclopramide, domperidone CT, T Gout medications (allopurinol, uricosurics, xanthine oxidase inhibitors) T, RCS Lithium CT Carbamazepine may cause clinically significant hyponatremia. Concomitant use with thiazide diuretics may potentiate hyponatremia. Intensified electrolyte depletion, particularly hypokalemia, may occur. Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gouttype complications. Thiazide diuretics may enhance the hyperglycemic effect of diazoxide. Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events. Bioavailability of thiazide diuretics may be increased by anticholinergic agents due to a decrease in gastrointestinal motility and gastric emptying. Conversely, prokinetic drugs may decrease the bioavailability of thiazide diuretics. Thiazide-induced hyperuricemia may compromise control of gout by allopurinol and probenecid. The co-administration of hydrochlorothiazide and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol. Thiazide diuretics reduce the doses of calcium supplements. Dose reduction or withdrawal of calcium and/or vitamin D supplements may be necessary. Monitor serum sodium levels. Use with caution. Monitor serum potassium, and adjust medications, as required. Monitor serum uric acid. Monitor serum glucose. Concomitant administration of hydrochlorothiazide and digoxin requires caution. Monitor electrolytes and digoxin levels closely. Supplement potassium or adjust doses of digoxin or thiazide, as required. Dose adjustment of thiazide may be required. Dosage adjustment of gout medications may be required. Concomitant use of Page 17 of 45 renal clearance of lithium and add a high risk of lithium toxicity. Medicinal products affecting serum potassium level CT, C The hypokalemic effect of diuretics may be synergetically aggravated by concomitant administration of kaliuretic diuretics, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives or antiarrhythmics, β2-agonists, pseudoephedrine, ephedrine, chloroquine, and antibiotics. Nonsteroidal antiinflammatory drugs (NSAID) CT NSAID-related retention of sodium and water antagonises the diuretic and antihypertensive effects of thiazides. Pressor amines (e.g. norepinephrine) T Selective serotonin reuptake inhibitors T, C (SSRIs, e.g. citalopram, escitalopram, sertraline) Skeletal muscle relaxants C of the curare family, eg., tubocurare Topiramate CT NSAID-induced inhibition of renal prostaglandins leading to decreases of renal blood flow, along with thiazide-induced decreases in GFR may lead to acute renal failure. Patients with heart failure may be at particular risk. Hydrochlorothiazide may reduce the response to pressor amines such as norepinephrine. Concomitant use with thiazide diuretics may potentiate hyponatremia. Thiazide drugs may increase the responsiveness of some skeletal muscle relaxants, such as curare derivatives Additive hypokalemia. Possible thiazide-induced increase in topiramate serum concentrations. thiazide diuretics with lithium is generally not recommended. If such use is deemed necessary, reduce lithium dose by 50% and monitor lithium levels closely. Monitoring of serum electrolyte balance is recommended. Simultaneous administration of potassium supplements may be necessary. If combination use is necessary, monitor renal function, serum potassium, and blood pressure closely. Dose adjustments may be required. The clinical significance of this effect is not sufficient to preclude their use. Monitor serum sodium levels. Use with caution. Monitor serum potassium and topiramate levels. Use potassium supplements, or adjust topiramate dose as Page 18 of 45 necessary. Legend: C = Case Study; RCS = Retrospective Cohort Study; CT = Clinical Trial; T = Theoretical Drug-Food Interactions DIOVAN®-HCT may be administered with or without food, however it should be taken consistently with respect to food intake (see DOSAGE AND ADMINISTRATION). DOSAGE AND ADMINISTRATION Dosing Considerations Dosage must be individualized. The fixed combination is not for initial therapy. The dose of DIOVAN®-HCT (valsartan and hydrochlorothiazide) should be determined by the titration of the individual components. Hepatic Impairment No initial dosage adjustment in valsartan is required in patients with mild to moderate hepatic impairment. Due to the hydrochlorothiazide component, DIOVAN®-HCT is not recommended in patients with severe hepatic impairment (see Warnings and Precautions). Because thiazide diuretics may precipitate hepatic coma, care should be exercised when administering a fixed combination product containing hydrochlorothiazide (see WARNINGS AND PRECAUTIONS). Due to the valsartan component, DIOVAN®-HCT should be used with particular caution in patients with biliary obstructive disorders (see Contraindications and Warnings and Precautions). Renal Impairment No dosage adjustment is required for patients with mild to moderate renal impairment (Glomerular Filtration Rate (GFR) ≥30 mL/min). Due to the hydrochlorothiazide component, DIOVAN®-HCT is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) and with anuria (see Contraindications) and should be used with caution in patients with severe renal impairment (GFR <30 mL/min) (see Warnings and precautions for use and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). Elderly No dosage adjustment is usually necessary however see WARNINGS AND PRECAUTIONS. Recommended Dose and Dosage Adjustment Once the patient has been stabilized on the individual components as described below, DIOVAN®-HCT tablet, 80mg/12.5mg, 160mg/12.5mg, 160 mg/25, 320mg/12.5mg, or 320mg/25mg once daily may be substituted if the doses on which the patient was stabilized are the same as those in the fixed combination (see INDICATIONS AND CLINICAL USE and WARNINGS AND PRECAUTIONS). Page 19 of 45 The maximum recommended dose is 320 mg valsartan and 25 mg hydrochlorothiazide and the titration will be based on physician’s judgment according to severity of hypertension and other associated risk factors. DIOVAN®-HCT may be administered with our without food, however it should be taken consistently with respect to food intake. Valsartan monotherapy The recommended starting dose of DIOVAN® is 80 mg once daily. The antihypertensive effect is present within 2 weeks and maximal reduction is usually attained within 4 weeks following initiation of therapy. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to a maximum of 320 mg or a thiazide diuretic added. Diuretic-Treated Patients In patients receiving diuretics, valsartan therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional anti-hypertensive therapy. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of DIOVAN®-HCT to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS). If this is not possible because of the patient’s condition, DIOVAN®-HCT should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient. Missed Dose Patients should try to take their dose at the same time each day, preferably in the morning. However, if they have forgotten to take the dose during the day, they should carry on with the next dose at the usual time. They should not double doses. OVERDOSAGE No specific information is available on the treatment of overdosage with DIOVAN®-HCT (valsartan and hydrochlorothiazide). Treatment is symptomatic and supportive. For management of a suspected drug overdose, contact your regional Poison Control Centre. Valsartan Limited data are available in regard to overdosage with DIOVAN® (valsartan) in humans. The most likely manifestations of overdosage would be hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock, and/or tachycardia. If symptomatic hypotension should occur, supportive treatment should be instituted. Valsartan is not removed from the plasma by dialysis. Page 20 of 45 Hydrochlorothiazide The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. ACTION AND CLINICAL PHARMACOLOGY DIOVAN®-HCT (valsartan and hydrochlorothiazide) combines the actions of valsartan, an orally active angiotensin II AT1 receptor blocker, and that of a diuretic, hydrochlorothiazide. Mechanism of Action Valsartan Valsartan acts selectively on AT1, the receptor subtype that mediates the known cardiovascular actions of angiotensin II, the primary vaso-active hormone of the renin-angiotensin-system. The AT2 receptor subtype, found in tissues such as brain, endometrium, myometrium and fetal kidney and adrenals, plays no known role in cardiovascular homeostasis to date. Valsartan does not exhibit any partial AT1 receptor agonist activity and has essentially no activity at the AT2 receptor. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The primary metabolite, valeryl 4-hydroxy valsartan, is essentially inactive. Angiotensin II has a wide variety of physiological effects; many are either directly or indirectly involved in blood pressure regulation. A potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition it promotes sodium retention and aldosterone secretion. Blockade of angiotensin II AT1 receptors results in two- to three-fold increase in plasma renin and angiotensin II plasma concentrations in hypertensive patients. Long-term effects of increased AT2 receptor stimulation by angiotensin II are unknown. Valsartan does not inhibit angiotensin converting enzyme (ACE), also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin. Hydrochlorothiazide Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, therefore co-administration of an angiotensin II AT1 Receptor Blocker tends to reverse the potassium loss associated with thiazide diuretics. Page 21 of 45 Hydrochlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs. Hydrochlorothiazide does not affect normal blood pressure. Pharmacodynamics Valsartan Valsartan inhibits the pressor effect of an angiotensin II infusion. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. After a single oral dose, the antihypertensive activity of valsartan has an onset within approximately 2 hours and peaks within 4-6 hours in most patients. The anti-hypertensive effect of valsartan persists for 24 hours after dosing. Trough/peak ratio ranges from 0.54 to 0.76. Valsartan reduces blood pressure in hypertensive patients without affecting heart rate. During repeated dosing, the maximum blood pressure reduction with any dose is generally attained within 4 weeks, and is sustained during long-term therapy. Combinations with hydrochlorothiazide produce additional reduction in blood pressure. There is no apparent rebound effect after abrupt withdrawal of valsartan therapy. Although data available to date indicate a similar pharmacodynamic effect of valsartan in black and white hypertensive patients, this should be viewed with caution since antihypertensive drugs that affect the renin-angiotensin system, such as ACE inhibitors and angiotensin II AT1 receptor blockers, have generally been found to be less effective in low-renin hypertensives (frequently blacks). Hydrochlorothiazide Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6-12 hours. Valsartan-Hydrochlorothiazide The components of DIOVAN®-HCT have been shown to have additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component used alone. The antihypertensive effect of DIOVAN®-HCT is sustained for a 24-hour period. In clinical studies of at least one year duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of DIOVAN®-HCT had no clinically significant effect on heart rate. Page 22 of 45 Pharmacokinetics Valsartan Since its pharmacokinetics are linear in the 80 to 320 mg dose range, valsartan does not accumulate appreciably in plasma following repeated administration. Plasma concentrations are similar in males and females. Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2 -4 hours. The mean absolute bioavailability of valsartan is about 23%, but with high variability. Distribution: Valsartan is 94-97% bound to serum protein, mainly serum albumin. The steadystate volume of distribution of valsartan after intravenous administration is about 17 L, indicating that valsartan is not distributed into tissues extensively. Metabolism: Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive. Valsartan biotransformation does not seem to involve the cytochrome P-450 system. The enzyme(s) responsible for valsartan metabolism have not been identified. Excretion: Following intravenous administration, valsartan shows bi-exponential decay kinetics (t1/2α <1 hour and t1/2β between 5-9 hours). Following administration of an oral solution of 14C labeled valsartan, 83% of absorbed valsartan is primarily excreted in the feces and 13% in the urine, mainly as unchanged compound. Following intravenous administration, plasma clearance of valsartan is about 2 L/h. The half-life of valsartan is 6 hours. Hydrochlorothiazide Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2 h).The increase in mean AUC is linear and dose proportional in the therapeutic range. Concomitant administration with food has been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of hydrochlorothiazide is 70 % after oral administration. Distribution: The distribution and elimination kinetics have generally been described as a biexponential decay function. The apparent volume of distribution is 4-8 L/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma. Metabolism: Hydrochlorothiazide is eliminated predominantly as unchanged drug. Excretion: Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of Page 23 of 45 hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. There is more than 95 % of the absorbed dose being excreted as unchanged compound in the urine. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. Valsartan- Hydrochlorothiazide The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with valsartan. The kinetics of valsartan are not markedly affected by the co-administration of hydrochlorothiazide. This observed interaction has no impact on the combined used of valsartan and hydrochlorothiazide. Special Populations and Conditions Pediatrics: The pharmacokinetics of valsartan have not been investigated in patients <18 years of age. Geriatrics: Exposure to valsartan is about 50% higher as measured by AUC and Cmax and the half life is longer in elderly subjects than in young subjects. However, this difference has not been shown to have any clinical significance. Gender: Plasma concentrations are similar in males and females. Hepatic Insufficiency: On average, patients with mild to moderate chronic liver disease have twice the exposure to valsartan of healthy volunteers as measured by AUC and Cmax (see WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION). DIOVAN®-HCT should be used with particular caution in patients with biliary obstructive disorders. Because of hydrochlorothiazide, DIOVAN®-HCT is not recommended in patients with severe hepatic impairment (see Warnings and Precautions, Hepatic/Biliary/Pancreatic). Renal Insufficiency: Renal clearance accounts for only 30% of total plasma clearance. There is no apparent correlation between renal function and exposure to valsartan, as measured by AUC and Cmax, in patients with different degrees of renal impairment. In patients with renal failure undergoing hemodialysis, limited information showed that exposure to valsartan is comparable to that in patients with creatinine clearance > 10 mL/min. In the patients with moderate to severe renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased by 2.27 fold and 8.46 fold respectively and the mean cumulative urinary excretion rate is reduced by 35% as compared to baseline 51% of the oral dose. As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide. Therefore, DIOVAN®-HCT is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min). Page 24 of 45 Valsartan is not removed from plasma by dialysis. STORAGE AND STABILITY Protect from moisture. Store at 15 - 30°C. SPECIAL HANDLING INSTRUCTIONS Not applicable. DOSAGE FORMS, COMPOSITION AND PACKAGING Availability Pr DIOVAN®-HCT (valsartan and hydrochlorothiazide) tablets, 80mg/12.5mg are supplied in cartons containing 2 blister strips of 14 tablets. Pr DIOVAN®-HCT (valsartan and hydrochlorothiazide) tablets, 160mg/12.5mg are supplied in cartons containing 2 blister strips of 14 tablets. Pr DIOVAN®-HCT (valsartan and hydrochlorothiazide) tablets, 160mg/25mg are supplied in cartons containing 2 blister strips of 14 tablets. Pr DIOVAN®-HCT (valsartan and hydrochlorothiazide) tablets, 320mg/12.5mg are supplied in cartons containing 2 blister strips of 14 tablets. Pr DIOVAN®-HCT (valsartan and hydrochlorothiazide) tablets, 320mg/25mg are supplied in cartons containing 2 blister strips of 14 tablets. Composition DIOVAN®-HCT (valsartan and hydrochlorothiazide) Tablet, 80mg/12.5mg Each light orange, ovaloid, film-coated tablet imprinted with HGH on one side and CG on the other contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose. The coating contains hydroxypropyl methylcellulose, polyethylene glycol, red iron oxide, talc, titanium dioxide and yellow iron oxide. DIOVAN®-HCT (valsartan and hydrochlorothiazide) Tablet, 160mg/12.5mg Each dark red, ovaloid, film-coated tablet imprinted with HHH on one side and CG on the other contains 160 mg of valsartan and 12.5 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose. The coating contains hydroxypropyl methylcellulose, polyethylene glycol, red iron oxide, talc, and titanium dioxide. Page 25 of 45 DIOVAN®-HCT (valsartan and hydrochlorothiazide) Tablet, 160mg/25mg Each brown, ovaloid, film-coated tablet imprinted with HXH on one side and NVR on the other contains 160 mg of valsartan and 25 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose. The coating contains hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, talc, and titanium dioxide and yellow iron oxide. DIOVAN®-HCT (valsartan and hydrochlorothiazide) Tablet, 320mg/12.5mg Each pink, ovaloid, film coated tablet imprinted with “NVR” on one side and “HIL” on the other contains 320 mg of valsartan and 12.5 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose. The coating contains hydroxypropyl methylcellulose, polyethylene glycol, red iron oxide, black iron oxide, talc, and titanium dioxide. DIOVAN®-HCT (valsartan and hydrochlorothiazide) Tablet, 320mg/25mg Each yellow, ovaloid, film coated tablet imprinted with “NVR” on one side and “CTI” on the other contains 320 mg of valsartan and 25 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose. The coating contains hydroxypropyl methylcellulose, polyethylene glycol, yellow iron oxide, talc, and titanium dioxide. Page 26 of 45 PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Proper Names: valsartan hydrochlorothiazide Chemical Names: (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl}-valine 6-chloro-3,4-dihydro-2H-1,2,4benzothiazidine-7-sulfonamide 1,1-dioxide Molecular formulae: C24H29N5O3 C7H8ClN3O4S2 Molecular weights: 435.5 297.74 Structural formulae: Description: Fine white to practically white, practically odourless powder. It is soluble in ethanol, methanol and slightly soluble in water. White, or practically white, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution and dimethyl sulfoxide, sparingly soluble in methanol and ethanol; practically insoluble in diethyl ether. Page 27 of 45 CLINICAL TRIALS In controlled clinical trials including over 7600 patients with essential hypertension, 4372 patients were exposed to valsartan (80, 160 and 320 mg) and concomitant hydrochlorothiazide (12.5 and 25 mg). Two randomized, double-blind factorial trials compared various combinations of 80/12.5 mg, 80/25 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25 mg with their respective components and placebo. The combination of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 14-21/8-11 mmHg at 80/12.5 mg to 320/25 mg, compared to 7- 10/4-5 mmHg for valsartan 80 mg to 320 mg and 5-11/2-5 mmHg for hydrochlorothiazide 12.5 mg to 25 mg, alone. Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not respond to adequately to valsartan 80 mg to valsartan 320 mg, resulted in the additional lowering of systolic and diastolic blood pressure by approximately 4-12/2-5 mmHg. The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time point at which blood pressure was measured in these trials. In one year open label follow up study (without placebo control) the effect of the combination of valsartan and hydrochlorothiazide was maintained. The antihypertensive effect was independent of age or gender. The overall response to the combination was similar for black and non-black patients. There was essentially no change in heart rate in patients treated with the combination of valsartan and hydrochlorothiazide in controlled trials. DETAILED PHARMACOLOGY Pharmacodynamics The in vitro data support that valsartan is a specific antagonist of the AT1 sub-type receptor, that valsartan does not react at other receptor sites and has an affinity for the receptor that is similar in the rat, marmoset and human; whereas the affinity of valsartan for the AT1 sub-type receptor in the dog is significantly smaller. This is further reinforced by data from in vivo studies and the literature. From animal and human studies, there is also no evidence that AT1 receptor blockade by valsartan together with the resulting Ang II increase causes any arrhythmogenic effects. Vascular reactivity in the rat to exogenous Ang II is attenuated by sodium restriction and increased during sodium loading. These effects are opposite to those exhibited by the adrenal glomerulosa where sensitivity to Ang II increases during sodium restriction. This phenomenon is the consequence of changes in circulating Ang II levels linked to the altered sodium balance. As expected, in rats, after treatment with valsartan, there is a high level of circulating Ang II, so a down regulation of the receptor could therefore be expected which would reduce the efficacy of valsartan, but vascular receptor density and therefore vascular reactivity in the liver does not decrease after chronic treatment. So valsartan, should not produce internalisation of the Ang II receptor and hence, tolerance. With the increase in circulating Ang II, there is the possibility of some effects through stimulation of the AT2 receptor. The role of the AT2 receptor is currently unknown. No untoward effects were noted in preclinical or clinical studies that might suggest an AT2 receptor mediated action. Page 28 of 45 The correlation between plasma levels and pharmacological response is not very clear. A similar effect is also seen in the clinic where there is also not a very clear relationship between plasma levels and blood pressure reduction. The variability of the plasma levels is most likely due to the variability in absorption which is pH dependent and thus there will be a limited window of absorption in the alimentary tract. However the critical factor in the relationship between plasma drug levels and effect is that once the AT1 receptors are blocked, increasing plasma concentrations produce very little further action. Therefore this individual variability is not of major importance. Pharmacokinetics Results from the absorption, distribution, metabolism and excretion studies show a fairly similar pattern for the rat, marmoset and human though the volume of distribution is greater in the two former species. In the rat the distribution is rapid and valsartan is found mainly in the blood, plasma, liver, lung and renal cortex. In all 3 species the extent of protein binding is comprised between 94% and 97% and the metabolism is fairly low (> 10%) with excretion mainly via the bile. The vast majority of the dose is cleared within 24 hours and there does not appear to be any accumulation on repeated dosing. It does not cross the blood/brain barrier or transfer into the foetus. TOXICOLOGY Acute Toxicity Valsartan Species Route Dose mg/kg Major findings Rat Gavage 100 No adverse findings. Rat Gavage 1000, 2000 2000 mg/kg: Diarrhea, white substance (similar to test substance) in feces. Approximate LD50 >2000 mg/kg. Marmoset Gavage 600, 1000 No effect 600 mg/kg. 1000 mg/kg: Vomiting, white substance (similar to test substance) in vomitus. Approximate LD50 >1000 mg/kg. Valsartan and hydrochlorothiazide Species Rat Route Gavage Dose (mg/kg) valsartan HCTZ 1524 476 Major Findings No adverse findings. Approximate LD50 > 1524.0:476.0 mg/kg Page 29 of 45 Marmoset Gavage 320.0 761.9 100.0 238.1 No adverse findings Approximate LD50 > 761.9:238.1 mg/kg Long-Term Toxicity Valsartan In toxicity studies conducted in several animal species, the main preclinical safety findings involving the kidney and related effects, are attributed to the pharmacological action of the compound. In preclinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. Species Route Duration Dose mg/kg Major findings Rat Gavage 14 day 60, 200, 600 Mid & High dose groups: ↑ urea NOEL = 60 mg/kg. Marmoset Gavage 14 day 60, 200, 600 Rat Intravenous 14 day 10, 30, 100 High dose group: Vomiting and mild to moderate ↑ in urea NOEL = 200 mg/kg. No adverse findings. NOAEL = 100 mg/kg. Marmoset Intravenous 14 day 6, 20, 60 No adverse findings. NOAEL = 60 mg/kg. Rat Gavage 91 day 60, 200, 600 Mid & High dose groups: ↑ urea High dose group: Renal tubular hyperplasia, glomerular arteriolar hypertrophy. Anemia with regenerative response. NOEL = 60 mg/kg. Page 30 of 45 Species Route Duration Dose mg/kg Major findings Marmoset Gavage 91 day 30, 60, 200, 600 400 Plasma urea & creatinine ↑ from 200 mg/kg. Nephropathy at 200 & 600 mg/kg. Alk. Phos. ↑ at 400 mg/kg. Anemia from 200 mg/kg. Hypertrophy of glomerular arteriole at 400 mg/kg. Adrenal cortex hypertrophy from 200 mg/kg in F. Cachexia including 3 deaths at 600 mg/kg. One death at 200 mg/kg. One death at 400 mg/kg during the recovery period. NOEL = 60 mg/kg. Rat Gavage 12 months 20, 60, 200 Marmoset Gavage 12 months 12, 40, 120 Mid dose group: ↑ urea at 60 mg/kg High dose group: anemia & renal arteriolar hypertrophy. NOAEL = 20 mg/kg. Mid & High dose groups: ↑ in urea and creatinine NOAEL = 12 mg/kg. NOEL No observable effect level. NOAEL No observable adverse effect level. Valsartan and hydrochlorothiazide The combination of valsartan/hydrochlorothiazide was evaluated for toxicity in the rat and marmoset for up to 6 months. Treatment-related findings were mainly related to the exaggerated pharmacological effects of valsartan and/or hydrochlorothiazide and consisted of reduction in red cells parameters, alterations in electrolyte and water concentrations in the body, hypertrophy of the juxtaglomerular apparatus and renal tubular changes. The marmoset was a much more sensitive species in which there was an approximate 10-fold potentiation of blood pressure reduction with the combination of valsartan and hydrochlorothiazide as compared to valsartan alone. Hydrochlorothiazide alone had no effect on the blood pressure of marmosets. This potentiation has not been seen in the human subject; the effect of valsartan and hydrochlorothiazide is additive. Species Marmoset Route Gavage Duratio n 14 days Dose (mg/kg) valsartan HCTZ -100 -300 -1000 Major findings No adverse findings. All groups: ↓ Plasma Na+ and K+ Page 31 of 45 Rat Gavage 1 month 50.0 200.0 600.0 -30.0 120.0 400.0 -- Marmoset Gavage 1 month Rat Gavage 6 months 30.0 100.0 300.0 -- Marmoset Gavage 6 months 30.0 60.0 120.0 240.0→1 20.0 Marmoset Gavage 6 months 3.0 10.0 30.0 15.625 62.5 187.5 187.5 9.375 37.5 125 125 All groups: Pharmacological doserelated findings; ↑ in urea. NOAEL > 600.0:187.5 mg/kg High dose group: Early death of all 3 F. High dose and HCTZ groups: Renal changes including tubular basophilia Low and mid dose groups: Minor pharmacological dose-related changes. NOAEL = 30.0:9.375 mg/kg 9.375 All groups: Pharmacological dose31.25 related findings; ↑ urea. 93.75 High dose group: Changes in plasma 93.75 lipid parameters. NOAEL = 100.0:31.25 mg/kg 9.375 All dose levels (not HCTZ): Deaths 18.75 associated with renal changes related 37.5 to severe pharmacological effects. 75.0→37. HCTZ: Minor effects. 5 NOAEL not identified. 75.0 0.93 No adverse findings 3.125 NOAEL=10.0:3.125 9.325 NOAEL: No Observed Adverse Effect Level NOEL: No Observed Effect Level Reproduction and Teratology Valsartan In reproductive studies in rats, mice and rabbits, only minor effects were noted. In rabbits there was evidence of low fetal weights, litter loss and abortion, but no teratogenicity at 5 and 10 mg/kg. Rabbits are extremely susceptible to compounds acting on the RAAS so this finding is not unexpected. There was also a slightly reduced postnatal F1 survival and development together with reduced maternal bodyweight gain in rats at 600 mg/kg. Otherwise, there was no effect at the highest doses tested on fertility, reproductive performance in rats (200 mg/kg), embryotoxcity, fetotoxicity, teratogenicity in rats and mice (600 mg/kg). In embryofetal development studies (Segment II) in mice rats and rabbits, fetotoxicity was observed in association with maternal toxicity in rats and valsartan doses of > 200 mg/kg/days and in rabbits at doses of > 10 mg/kg/day. In a peri- and postnatal development toxicity (segment III) study, the offsprings from rats treated at 600 mg/kg during the last trimester and during lactation showed a slightly reduced survival rate and a slight developmental delay (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women). Page 32 of 45 Segment I Species Route Duration of dosing Dose mg/kg Major findings Rat Gavage M: 90 days F: day 14 to 19 or 14 to +20 10, 50, 200 High dose: ↓ in field motor actvity in F; no effect on fertility, reproductive performance in F0 & F1 and on F1 development. No effect on kidney development. Segment II Species Route Duration of dosing Gavage Day 6 to 15 Dose mg/kg 60, 200, 600 Major Findings Rat Gavage Day 6 to 15 60, 200, 600 Mid & High dose groups:↓ maternal body weight gain High dose group: ↓ fetal weights All dose groups: No embryotoxicity, fetotoxicity or teratogenicity Rabbit1 Drench 2.5, 15, 30, 45, 50, 150 Litter losses and deaths at 15 mg/kg and above. One litter loss (1/5) at 2.5 mg/kg. Rabbit Gavage Day 6 to 18 Day 7 to 19 2, 5, 10 Mid dose group: ↑ incidence of low fetal weights Mid & High dose groups: Litter loss and abortion All dose groups: No teratogenicity. Mouse Day 6 to 18 All dose groups: No embryotoxicity, fetotoxicity or teratogenicity. 1. Range Finding Segment III Rat Gavage Day 15 to 60, 200, 20 or 600 + 20 High dose group: Slightly reduced post-natal F1 survival and development in the presence of reduced maternal body weight gain. No effect on kidney development. + - Number of days post-parturition Valsartan and hydrochorothiazide Reproductive studies with the combination of valsartan/hydrochlorothiazide were conducted in rats, mice and rabbits. In all 3 species, there was no evidence of teratogenicity. In rats, there were maternal changes, mainly decreased food consumption, bodyweight or bodyweight gain at Page 33 of 45 50:115.6 mg/kg and above and deaths at 200:62.5 mg/kg and above. Fetotoxicity was seen at 262.5 mg/kg and above. This was considered to be related to the maternal toxicity. No effects were noted in mice at 600:187.5 mg/kg. Rabbits showed similar effects to those of valsartan alone at equivalent doses. Segment II Species Route Duration Dose (mg/kg) Valsartan HCTZ Rat Gavage Day 6 to 15 50.0 200.0 600.0 15.6 62.5 187.5 187.5 Rat Gavage Day 6 to 15 10.0 25.0 100.0 3.1 7.8 31.3 31.3 Rabbit Gavage Day 7 to 19 1.0 3.0 10.0 0.3 0.9 3.1 3.1 Mouse Gavage Day 6 to 15 50 200 600 15.6 62.5 187.5 187.5 Major Findings All dose groups: Maternal & fetal toxicty, ↓ food consumption, body weight & weight gain Mid dose & High dose groups: Maternal deaths (3/26 & 11/26), salivation and stool changes and ↓ fetal weight No embryotoxicity or teratogenicity. High dose group:↓ food consumption and weight gain No evidence of embryo- & feto-toxicity or embryotoxicity NOEL (maternal): 25.0:7.8 mg/kg NOEL (fetal): 100:31.3 mg/kg All dose groups: Slightly ↓ food consumption Mid dose group: Maternal death (1/18) High dose group: ↑ no. of late resorptions, total resorptions, mean & % post implantation loss; slight ↓ in no. of live fetuses. No evidence of teratogenecity NOAEL (fetal): 3.0:0.9 mg/kg No maternal effects, embryo-, fetotoxicity or teratogenicity. NOAEL (fetal & Maternal): 600.0:187.5 mg/kg Mutagenicity Valsartan Valsartan has been tested for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results. Page 34 of 45 In vitro Test System μg/mL or *plate Comments Mutagenicity Bacteria** Mutagenicity Bacteria*** *5000.0 Negative Gene mutation Chinese hamster cells (V79) 81.88 - Negative 5550.00 Chromosome aberration Chinese hamster cells (ovary) 81.88 - Negative 1310.00 *5.0 - 5000.0 Negative In-vivo Test System mg/kg Comments Micronucleus Rat 781.3 - 3 125.0 Negative ** S typhimurium - TA98, TA100, TA 1537 E coli - WP2uvrA *** S typhimurium - TA98, TA100, TA1535, TA 1537 E coli - WP2uvrA Carcinogenicity Valsartan Species Route Mouse Diet Duratio n 2 years Rat Diet 2 years Dose (mg/kg) 10, 40, 160 10, 50, 200 Major Findings Hyperplasia of gastric mucosa in males. ↓ body weight gain at ≥10 mg/kg. No carcinogenic effect ↓ body weight gain, anemia, nephropathy at ≥ 50 mg/kg. ↑ urea and creatinine, ↓ total proteins and albumin at 200 mg/kg. No carcinogenic effect. Page 35 of 45 REFERENCES 1. Benz J, Oshrain C, et al. Valsartan, a new Angiotensin II receptor antagonist: A doubleblind study comparing the incidence of cough with Lisinopril and Hydrochlorothiazide. J Clin Pharmacol 1997; 37: 101-107. 2. Beerman B and Groschinsky-Grand M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol. 1977; 12: 297-303. 3. Beerman B, Groschinsky-Grand M and Rosen A. Absorption, metabolism, and excretion of hydrochlorothiazide. Clin Pharmacol Ther. 1975; 19: 531-537. 4. Black HR, Graff A, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: Efficacy, tolerability and safety compared to an angiotensinconverting enzyme inhibitor, lisinopril. J of Human Hypertension 1997; 11: 483-489. 5. Bremner AD, Mehring GH and Meilenbrock S. Long-term systemic tolerability of valsartan compared with lisinopril in elderly hypertensive patients. Advances in Therapy 1997; 14 (5): 245- 253, 1997. 6. Bucher JR. NTP technical report on the toxicology and carcinogenesis studies of hydrochlorothiazide (CAS no. 58-93-5) in F344/N rats and B6C3F1 mice (feed studies). NTP TR 357. NIH publication No. 89-2812. July 1989. US Department of Health and Human Services. 7. Holwerda NJ, Fogari R, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: Efficacy and safety compared with placebo and enalapril. J of Hypertension. 1996; 14: 1147-1151. 8. Mallion J-M, Boutelant S, et al. Valsartan, a new angiotensin II antagonist; blood pressure reduction in essential hypertension compared with an angiotensin converting enzyme inhibitor, enalapril. J Blood Pressure Monitoring. 1997; 2 (3-4): 1-5. 9. Neutel J, Weber M, et al. Valsartan, a new angiotensin II antagonist: Antihypertensive effects over 24 hours. Clin Therapeutics. 1997; 19 (3): 447-458. 10. Oparil S, Dyke S, et al. The efficacy and safety of valsartan compared with placebo in the treatment of patients with essential hypertension. Clin Therapeutics. 1996; 18 (5): 797-810. Page 36 of 45 IMPORTANT: PLEASE READ PART III: CONSUMER INFORMATION Pr DIOVAN®-HCT valsartan and hydrochlorothiazide tablets Read this carefully before you start taking DIOVAN®-HCT and each time you get a refill. This leaflet is a summary and will not tell you everything about DIOVAN®-HCT. Talk to your doctor, nurse, or pharmacist about your medical condition and treatment and ask if there is any new information about DIOVAN®-HCT. ABOUT THIS MEDICATION What the medication is used for: DIOVAN®-HCT lowers high blood pressure. High blood pressure increases the workload of the heart and arteries. If this condition continues for a long time, damage to the blood vessels of the brain, heart, and kidneys can occur, and may eventually result in a stroke, heart failure or kidney failure. High blood pressure also increases the risk of heart attacks. Reducing your blood pressure decreases your risk of developing these illnesses. What it does: DIOVAN®-HCT contains a combination of 2 drugs, valsartan and hydrochlorothiazide: Valsartan is an angiotensin receptor blocker (ARB). You can recognize an ARB because its medicinal ingredient ends in “-SARTAN”. It lowers blood pressure. DIOVAN®-HCT does this by specifically blocking angiotensin II. Angiotensin II is a natural hormone produced in the body to keep blood pressure at normal levels. One function of angiotensin II is to increase blood pressure, usually when it becomes too low. Valsartan works by blocking the effect of angiotensin II. As a result, blood pressure is lowered. Hydrochlorothiazide is a diuretic or “water pill” that increases urination. This lowers blood pressure. Together valsartan and hydrochlorothiazide lower blood pressure. This medicine does not cure high blood pressure. It helps to control it. Therefore, it is important to continue taking DIOVAN®-HCT regularly even if you feel fine. If you have any questions about how DIOVAN®-HCT works or why this medicine has been prescribed for you, ask your doctor. When it should not be used: Do not take DIOVAN®-HCT if you: Are allergic to valsartan, hydrochlorothiazide or to any non-medicinal ingredient in the formulation. Are allergic to any sulfonamide-derived drugs (sulfa drugs); most of them have a medicinal ingredient that ends in “-MIDE”. Ask your physician or pharmacist if you are not sure what sulfonamide-derived drugs are. Have experienced an allergic reaction (angioedema) with swelling of the hands, feet, or ankles, face, lips, tongue, throat, or sudden difficulty breathing or swallowing to any ARB. Be sure to tell your doctor, nurse, or pharmacist that this has happened to you. Have difficulty urinating or produce no urine. Suffer from severe liver disease with destruction of the small bile ducts within the liver (biliary cirrhosis) leading to the builds up bile in the liver (cholestasis). Are taking a medicine that contains aliskiren (such as RASILEZ®) and you have diabetes or kidney disease. Are pregnant or intend to become pregnant. Taking DIOVAN®-HCT during pregnancy can cause injury and even death to your baby. Are breastfeeding. DIOVAN®-HCT passes into breast milk. Have one of the following rare hereditary diseases: o Galactose intolerance o Lapp lactase deficiency o Glucose-galactose malabsorption Because lactose is a non-medicinal ingredient in DIOVAN®-HCT. Have serious kidney disease. Have a too low level of potassium or sodium or if you have a too high level of calcium in your blood despite treatment. Have uric acid crystals in the joints (gout). Page 37 of 45 IMPORTANT: PLEASE READ Are under 18 years old. If either of these apply to you, tell your doctor without taking DIOVAN® -HCT. What the medicinal ingredients are: Valsartan and hydrochlorothiazide. What the non-medicinal ingredients are: DIOVAN®-HCT tablets: Colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. In addition, the tablets also contain: DIOVAN®-HCT 80/12.5 mg: Red and yellow iron oxide DIOVAN®-HCT 160/12.5 mg: Red iron oxide DIOVAN®-HCT 160/25 mg: Red, yellow and black iron oxide DIOVAN®-HCT 320/12.5 mg: Red and black iron oxide DIOVAN®-HCT 320/25 mg: Yellow iron oxide If you are on a special diet, or if you are allergic to any substance, ask your doctor or pharmacist whether any of these ingredients may cause a problem. What dosage forms it comes in: Film-coated tablets, 80/12.5 mg (light orange), 160/12.5 mg (dark red), 160/25 mg (brown), 320/12.5 mg (pink), and 320/25 mg (yellow). WARNINGS AND PRECAUTIONS Serious Warnings and Precautions - Pregnancy DIOVAN®-HCT should not be used during pregnancy. If you discover that you are pregnant while taking DIOVAN®-HCT, stop the medication and contact your doctor, nurse, or pharmacist as soon as possible. BEFORE you use DIOVAN®-HCT talk to your doctor, nurse, or pharmacist if you: Are allergic to any drug used to lower blood pressure, including angiotensin converting enzyme (ACE) inhibitors, or penicillin. Have narrowing of an artery or a heart valve. Have heart failure. Have diabetes, liver or kidney disease. Have lupus or gout. Are on dialysis. Are dehydrated or suffer from excessive vomiting, diarrhea, or sweating. Are taking a salt substitute that contains potassium, potassium supplements, or a potassium-sparing diuretic (a specific kind of “water pill”). Are on a low-salt diet. Are less than 18 years old. Suffer from severe liver disease with destruction of the small bile ducts within the liver (biliary cirrhosis) leading to the builds up bile in the liver (cholestasis); Ever had swelling mainly of the face and throat while taking other drugs (including an ACEinhibitor). If you get those symptoms, stop taking DIOVAN®-HCT and contact your doctor straight away. You should never take DIOVAN® -HCT again; Have low levels of potassium in your blood (with or without symptoms such as muscle weakness, muscle spasms, abnormal heart rhythm). Have low levels of sodium in your blood (with or without symptoms such as tiredness, confusion, muscle twitching, convulsions). Have high levels of calcium in your blood (with or without symptoms such as nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching). Have high levels of uric acid in the blood. Are suffering from allergy or asthma have high levels of cholesterol or triglycerides in your blood; Are suffering from vomiting or diarrhea, or taking high doses of a diuretic (water pill); Are taking a medicine that contains aliskiren, such as RASILEZ®, used to lower high blood pressure. The combination with DIOVAN®-HCT is not recommended. Are taking an angiotensin converting enzyme (ACE) inhibitor. Page 38 of 45 IMPORTANT: PLEASE READ Hydrochlorothiazide in DIOVAN®-HCT can cause Sudden Eye Disorders: ● Myopia: sudden nearsightedness or blurred vision. ● Glaucoma: an increased pressure in your eyes, eye pain. Untreated, it may lead to permanent vision loss. These eye disorders are related and can develop within hours to weeks of starting DIOVAN®HCT. You may become sensitive to the sun while taking DIOVAN®-HCT. Exposure to sunlight should be minimized until you know how you respond. You should have regular blood tests before and during treatment with DIOVAN®-HCT. These will monitor the amount of electrolytes (such as potassium, sodium, calcium or magnesium) in your blood and may also monitor your kidney function You are pregnant, breast-feeding or thinking of becoming pregnant? Taking DIOVAN®-HCT during pregnancy can cause injury and even death to your baby. This medicine should not be used during pregnancy. If you are planning to become pregnant while taking DIOVAN®HCT, contact immediately your doctor. It is also advisable not to take DIOVAN®-HCT during breast-feeding. The diuretic component of DIOVAN®HCT passes into the breast milk and may also reduce your milk supply. If you are breast-feeding, avoid using DIOVAN®-HCT unless recommended by your doctor. Similar medicines were associated with serious harm to fetuses when they were taken during pregnancy. It is therefore important to tell your doctor immediately if you think you may have become pregnant, or planning to become pregnant. Your doctor will discuss with you the potential risk of taking DIOVAN®-HCT during pregnancy. Driving and using machines: Before you perform tasks which may require special attention, wait until you know how you respond to DIOVAN®-HCT. Dizziness, lightheadedness, or fainting can especially occur after the first dose and when the dose is increased. INTERACTIONS WITH THIS MEDICATION As with most medicines, interactions with other drugs are possible. Tell your doctor, nurse, or pharmacist about all medicines you take, including drugs prescribed by other doctors, vitamins, minerals, natural supplements, or alternative medicines. Certain medicines tend to increase your blood pressure, for example, non prescription preparations for appetite control, asthma, colds, coughs, hay fever and sinus problems. Before surgery and general anesthesia (even at the dentist’s office), tell the physician or dentist that you are taking DIOVAN®-HCT, as there may be a sudden drop in blood pressure associated with general anesthesia. The following may interact with DIOVAN®-HCT: Alcohol, barbiturates (sleeping pills), or narcotics (strong pain medications). They may cause low blood pressure and dizziness when you go from lying or sitting to standing up. Amphotericin B, an antifungal drug. Anticancer drugs, including cyclophosphamide and methotrexate. Antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), including citalopram, escitalopram, and sertraline. Antidiabetic drugs, including insulin and oral medicines. Bile acid resins used to lower cholesterol. Other blood pressure lowering drugs, including ACE inhibitors or aliskiren. Calcium or vitamin D supplements. Corticosteroids used to treat joint pain and swelling. Digoxin, a heart medication, or other digitalis glycosides. Drugs that slow down or speed up bowel function, including atropine, metoclopramide, and domperidone. Drugs used to treat epilepsy, including Page 39 of 45 IMPORTANT: PLEASE READ carbamazepine and topiramate. Gout medications, including allopurinol and probenecid. Lithium, antipsychotics, medicines used to treat some psychological conditions such as bipolar disease. Nonsteroidal anti-inflammatory drugs (NSAIDs), used to reduce pain and swelling. Examples include ibuprofen, naproxen, and celecoxib. Skeletal muscle relaxants used to relieve muscle spasms, including tubocurare. other diuretics (water pills), Pressor amines such as epinephrine (substances that raise blood pressure), Potassium-sparing agents Potassium supplement, salt substitutes containing potassium or other drugs that may increase potassium levels. Your doctor may monitor the levels of potassium in your blood periodically, Some antibiotics (rifamycin group), a drug used to protect against transplant rejection (cyclosporine) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of DIOVAN®-HCT. Amantadine (medicine to treat Parkinson's disease and also used to treat or prevent certain illnesses caused by viruses), Anticholinergic agents (medicines used to treat a variety of disorders such as gastrointestinal cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms, Parkinson's disease and as an aid to anaesthesia) Cortisone-like medicines, carbenoxolone (a medicine used to treat ulceration and inflammation), antibiotics such as penicillin G, antiarrhythmics (medicines used to treat heart problems), Cyclosporine (a medicine used in transplantation and in autoimmune disorders) Warfarin (medicine to prevent blood clot) Diazoxide (medicine to increase blood glucose level) Taking carbamazepine with hydrochlorothiazide (a medicinal ingredient in DIOVAN®-HCT) may cause a low sodium level in the blood. Symptoms of low sodium level in the blood may include: nausea, vomiting, headache, muscular cramps or weakness, and general uneasiness. As it worsens, confusion, decreased consciousness, convulsions (fits), or coma may occur. Tell your doctor if this happens to you. Sedatives, tranquilizers, narcotics, alcohol and analgesics may increase the blood-pressure lowering effect of DIOVAN®-HCT, so tell your physician or pharmacist if you are taking any of these. PROPER USE OF THIS MEDICATION Take DIOVAN®-HCT exactly as prescribed. It is recommended to take your dose at about the same time everyday. DIOVAN®-HCT can be taken with or without food. If DIOVAN®-HCT causes upset stomach, take it with food or milk. Patients who have high blood pressure often do not notice any signs or symptoms of this condition. So even though you are feeling well, your health may be getting worse. This makes it all the more important for you to continue your treatment program and to keep your appointments with your doctor. If you have any questions about how long to take DIOVAN®-HCT, talk to your doctor or your pharmacist. Usual Adult dose: Take DIOVAN®-HCT as directed. Dosage must be individualized. DIOVAN®-HCT is not for initial therapy. Once you are stabilized on both individual components of DIOVAN®-HCT the usual dosage is one 80 mg/12.5mg tablet once a day. In some cases, your doctor may prescribe a higher dose (e.g., the 160mg/12.5mg, 160 mg/25 mg, 320mg/12.5mg or the 320mg/25mg tablet). Overdose: If you experience severe dizziness and/or fainting, contact your doctor immediately so that medical attention may be given promptly. If you think you have taken too much DIOVAN®HCT contact your doctor, nurse, pharmacist, hospital Page 40 of 45 IMPORTANT: PLEASE READ emergency department or regional Poison control Centre immediately, even if there are no symptoms. Missed Dose: Try to take your dose at the same time each day, preferably in the morning. If you have forgotten to take your dose during the day, carry on with the next one at the usual time. Do not double doses. SIDE EFFECTS AND WHAT TO DO ABOUT THEM Side effects may include: back or leg pain, muscle cramps, spasms and pain, weakness, restlessness dizziness, pins and needles in your fingers, headache constipation, diarrhea, nausea, vomiting, decreased appetite, upset stomach, enlargement of the glands in your mouth bleeding under the skin, rash, red patches on the skin drowsiness, insomnia reduced libido joint pain Cough Fatigue (unusual tiredness or weakness, sometimes sign of potassium loss) Upper respiratory tract infection Blistering skin (sign of dermatitis bullous) If any of these affects you severely, tell your doctor, nurse or pharmacist. DIOVAN®-HCT can cause abnormal blood test results. Your doctor will decide when to perform blood tests and will interpret the results. SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Symptom / effect Talk with your doctor or pharmacist Only if severe Common Allergic reactions: Skin rash, skin eruption or other effect on the skin or eyes Low Blood Pressure: dizziness, fainting, lightheaded ness May occur when you go from lying or sitting to standing up. Decreased or increased levels of potassium in the blood: irregular heartbeats, muscle weakness and generally feeling unwell In all cases Stop taking drug and seek immediate help Page 41 of 45 IMPORTANT: PLEASE READ SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Uncommon Allergic Reaction: rash, hives, swelling of the face, lips, tongue or throat, difficulty swallowing or breathing Kidney Disorder: change in frequency of urination, nausea, vomiting, swelling of extremities, fatigue Liver Disorder: yellowing of the skin or eyes, dark urine, abdominal pain, nausea, vomiting, loss of appetite Increased blood sugar: frequent urination, thirst, and hunger SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Rare Electrolyte Imbalance: weakness, drowsiness, muscle pain or cramps, irregular heartbeat Abdominal pain Rhabdomyolysis: muscle pain that you cannot explain, muscle tenderness or weakness, dark brown urine Decreased White Blood Cells: infections, fatigue, fever, aches, pains, and flu-like symptoms Decreased Platelets: bruising, bleeding, fatigue and weakness Page 42 of 45 IMPORTANT: PLEASE READ SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Very rare Unknown Toxic Epidermal Necrolysis: severe skin peeling, especially in mouth and eyes Eye disorders: - Myopia: sudden near sightedness or blurred vision - Glaucoma: increased pressure in your eyes, eye pain Anemia: fatigue, loss of energy, weakness, shortness of breath. Inflammation of the Pancreas: abdominal pain that lasts and gets worse when you lie down, nausea, vomiting SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Rare or very rare Blistering skin reactions with symptoms such as rash, red skin, blistering of the lips, eyes or mouth, skin peeling and fever Possible signs of a blood disorder (symptoms like sore throat, fever, or chills) Jaundice: Yellow eyes or skin Irregular heart beat Necrotizing vasculitis; (Inflammation of vessels with or without pain) Tiredness, confusion, muscle twitching, convulsions (possible symptoms of hypernatre mia) Page 43 of 45 IMPORTANT: PLEASE READ SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Respiratory problems including pneumonitis and pulmonary edema Bone marrow failure, aplastic anemia: (Weakness, bruising and frequent infections) This is not a complete list of side effects. For any unexpected effects while taking DIOVAN®-HCT, contact your doctor, nurse, or pharmacist. HOW TO STORE IT Store your DIOVAN®-HCT tablets in a dry place at room temperature (15-30°C). Do not take DIOVAN®-HCT past the expiry date shown on the pack. Always remember This medicine has been prescribed to you for your current medical problem only. Do not give it to other people. It is very important that you take this medicine exactly as your doctor tells you in order to get the best results and reduce the chance of side effects. Keep out of reach and sight of children. REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: ------------------------------------------------------------------- Report online at www.healthcanada.gc.ca/medeffect Call toll-free at 1-866-234-2345 Complete a Canada Vigilance Reporting Form and: - Fax toll-free to 1-866-678-6789, or - Mail to: Canada Vigilance Program Health Canada Postal Locator 0701E Ottawa, Ontario K1A 0K9 Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at www.healthcanada.gc.ca/medeffect. NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice. MORE INFORMATION Please consult your doctor or pharmacist with any questions or concerns you may have regarding your individual condition. This document plus the full product monograph, prepared for health professionals can be found at: http://www.novartis.ca or by contacting the sponsor at: Novartis Pharmaceuticals Canada Inc. 385 Bouchard Blvd. Dorval, Quebec, H9S 1A9 1-800-363-8883 Page 44 of 45 IMPORTANT: PLEASE READ DIOVAN is a Registered Trademark This leaflet was prepared by Novartis Pharmaceuticals Canada Inc. Last revised: May 12, 2015 Page 45 of 45